1. Field of the Invention
This patent relates to a composition comprising oligonucleotides (oligos) that are anti-sense to adenosine receptors, and contain low amounts of or no adenosine (A). These agents are suitable for the treatment, among others, of pulmonary diseases associated with inflammation, impaired airways, including lung disease and diseases whose secondary effects afflict the lungs of a subject. Examples of these diseases are allergies, asthma, impeded respiration, allergic rhynitis, pain, cystic fibrosis, and cancers such as leukemias, e.g. colon cancer, and the like. The present agent may be administered prophylactically or therapeutically in conjunction with other therapies, or may be utilized as a substitute for therapies that have significant, negative side effects.
2. Background of the Invention
Respiratory ailments, associated with a variety of diseases and conditions, are extremely common in the general population, and more so in certain ethnic groups, such as African Americans. In some cases they are accompanied by inflammation, which aggravates the condition of the lungs. Asthma, for example, is one of the most common diseases in industrialized countries. In the United States it accounts for about 1% of all health care costs. An alarming increase in both the prevalence and mortality of asthma over the past decade has been reported, and asthma is predicted to be the preeminent occupational lung disease in the next decade. While the increasing mortality of asthma in industrialized countries could be attributable to the depletion reliance upon beta agonists in the treatment of this disease, the underlying causes of asthma remain poorly understood.
Adenosine may constitute an important mediator in the lung for various diseases, including bronchial asthma. Its potential role was suggested by the finding that asthmatics respond favorably to aerosolized adenosine with marked bronchoconstriction whereas normal individuals do not. An asthmatic rabbit animal model, the dust mite allergic rabbit model for human asthma, responded in a similar fashion to aerosolized adenosine with marked bronchoconstriction whereas non-asthmatic rabbits showed no response. More recent work with this animal model suggested that adenosine-induced bronchoconstriction and bronchial hyperresponsiveness in asthma may be mediated primarily through the stimulation of adenosine receptors. Adenosine has also been shown to cause adverse effects, including death, when administered therapeutically for other diseases and conditions in subjects with previously undiagnosed hyper reactive airways.
A handful of medicaments have been available for the treatment of respiratory diseases and conditions, although in general they all have limitations. Theophylline, an important drug in the treatment of asthma, is a known adenosine receptor antagonist which was reported to eliminate adenosine-mediated bronchoconstriction in asthmatic rabbits. A selective adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was also reported to inhibit adenosine-mediated bronchoconstriction and bronchial hyperresponsiveness in allergic rabbits. The therapeutic and preventative applications of currently available adenosine A1 receptor-specific antagonists are, nevertheless, limited by their toxicity. Theophylline, for example, has been widely used in the treatment of asthma, but is associated with frequent, significant toxicity resulting from its narrow therapeutic dose range. DPCPX is far too toxic to be useful clinically. The fact that, despite decades of extensive research, no specific adenosine receptor antagonist is available for clinical use attests to the general toxicity of these agents. Anti-sense oligonucleotides have received considerable theoretical consideration as potential useful pharmacological agents in human disease. Their practical application in actual models of human disease, however, has been somewhat elusive. One important impediment to their effective application has been a difficulty in finding an appropriate route of administration to deliver them to their site of action. Many in vivo experiments were conducted by administering anti-sense oligonucleotides directly to specific regions of the brain. These applications, however, necessarily have limited clinical utility due to their invasive nature. Although anti-sense oligonucleotides have received considerable theoretical consideration for their potential use as pharmacological agents in human disease, finding practical and effective applications for these agents in actual models of human disease, however, have been few and far between, particularly because they had to be administered in large doses. Another important consideration in the pharmacologic application of these molecules is their route of administration. Many in vivo applications have involved the direct administration of anti-sense oligonucleotides to limited regions of the brain. Such applications, however, have limited clinical utility due to their invasive nature. The systemic administration of anti-sense oligonucleotides as pharmacological agents has been found to have also significant problems, not the least of which being an inherent difficulty in targeting disease-involved tissues. That is, the necessary dilution of the anti-sense oligonucleotide in the circulatory system makes extremely difficult to attain a therapeutic dose at the target tissue by intravenous or oral administration. The bioavailability of orally administered anti-sense oligonucleotides is very low, of the order of less than about 5%. Anti-sense oligonucleotides have been used in therapy by many, including the present inventor, who in his previous work successfully treated various diseases and conditions by direct administration of these agents to the lung. In many instances, other workers have had to face the difficulties associated with the delivery of DNA molecules to a desired target. Thus, the route of administration may be of extreme importance for treating generalized diseases and conditions as well as those which are localized. In contrast, up to the present time, the delivery of anti-sense agents to the lung has been relatively undeveloped. As described by the present inventor in more detail below, the lung is an excellent target for the direct administration of anti-sense oligonucleotides and provides a non-invasive and a tissue-specific route.
Clearly, there exist presently no effective therapies for treating these ailments, or at least no therapics which are effective and devoid of significant detrimental side effects. Accordingly, there is still a need for an agent for the treatment of adenosine mediated ailments afflicting the pulmonary and respiratory ailments affecting the lung airways, including respiratory problems, bronchoconstriction, inflammation, allergy(ies), depletion or hyposecretion of surfactant, etc., which is highly effective and sufficiently selective to avoid detrimental side effects produced by other therapies. In addition, there is a definite need for making available a delivery method that will require low amounts of therapeutic agents and will be effective for the rapid and targeted access of tissue genes of mRNAs and the reversal of untoward effects afflicting a subject.